Project Summary The long-term objective of our work is to determine how the heparan sulfate / heparanase axis regulates tumor behavior and to use this knowledge to develop new therapies for cancer. We have demonstrated that the heparan sulfate proteoglycan syndecan-1 and heparanase work synergistically to condition the tumor microenvironment thereby promoting an aggressive tumor phenotype in myeloma and breast cancer two devastating cancers that home to and degrade bone. Our goal now is to determine the mechanism of heparanase activity in tumors and to target heparanase therapeutically using novel drugs. Although work in the field suggests that heparanase functions to degrade extracellular matrix and thereby promote tumor metastasis, based on our new discoveries we hypothesize that heparanase expression and activity initiates broad downstream effects that dramatically alter the tumor microenvironment to stimulate growth, angiogenesis, metastasis and osteolysis of bone-homing tumors. Data from in vivo models indicates that these events occur largely via heparanase-mediated upregulation of syndecan-1 shedding, enhanced MMP-9 expression and activated destruction of bone. The following specific aims will define the function and mechanism of action of heparanase in myeloma and breast cancer and test novel anti-heparanase drugs with the aim of eradicating these cancers. Aim 1 will determine the functional link between heparanase, syndecan-1 and MMP-9; Aim 2 will determine how heparanase enhances osteolysis; Aim 3 will test the anti-tumor efficacy and mechanism of action of a new class of heparin-based inhibitors of heparanase against breast cancer. These studies will utilize well-developed in vitro and in vivo models including the SCID-hu model in which human tumor cells are grown within human bone. This work will generate novel insight into heparanase function and mechanism of action and provide pre-clinical data necessary to drive new heparanase inhibitors toward clinical trials. Project Narrative Heparanase is a protein made by cancer cells that plays a major role in helping them grow and spread throughout the body. This project is designed to provide a new understanding about how heparanase works in multiple myeloma and breast cancer and to test new anti-heparanase drugs to block cancer growth.